RU2358716C2 - Organic compounds - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutics and concerns a solid pharmaceutical composition applicable for oral introduction and containing: (a) S1P receptor agonist; and (b) sugar alcohol.

EFFECT: invention provides homogeneous distribution of an active component in the solid composition with its high stability.

18 cl, 2 tbl, 39 ex

Description

The present invention relates to pharmaceutical compositions comprising a sphingosine-1 phosphate receptor agonist. Sphingosine-1-phosphate (hereinafter referred to as “S1P”) is a naturally occurring serum lipid. Currently, 8 S1P receptors are known, namely S1P1 - S1P8. S1P receptor agonists have the ability to accelerate homing of lymphocytes.

S1P receptor agonists are immunomodulators that cause lymphopenia due to the redistribution, preferably reversible, of lymphocytes from the bloodstream to the secondary lymphatic tissue, resulting in generalized immunosuppression. Unstimulated cells undergo destruction, stimulation of the migration of CD4 and CD8-T cells and B cells from the bloodstream to the lymph nodes (LN) and Peyer's plaques (PD) is stimulated, as a result of which cell infiltration into transplanted organs is inhibited.

Various known S1P receptor agonists have structural similarities, which causes related problems in creating the desired drug. First of all, there is a need for an S1P receptor agonist-containing preparation well adapted for oral administration in solid form, for example, in the form of a tablet or capsule.

Accordingly, the present invention provides a solid pharmaceutical composition for oral administration comprising an S1P receptor agonist and sugar alcohol.

When creating the invention, it was unexpectedly found that solid compositions containing sugar alcohol, allow you to create drugs that are best suited for oral administration of S1P receptor agonists. The compositions are a convenient tool for the systemic administration of S1P receptor agonists, do not have the disadvantages inherent in liquid preparations for injection or for oral administration, and have good physicochemical properties and storage ability. First of all, the compositions proposed in the present invention can be characterized by a high level of uniformity of distribution of the S1P receptor agonist in the composition, as well as high stability. The compositions of the invention can be prepared on high-speed automatic equipment and thus do not require manual capsulation.

S1P receptor agonists are typically sphingosine analogues, such as 2-substituted 2-aminopropane-1,3-diol or 2-aminopropanol derivatives. Examples of suitable S1P receptor agonists are, for example, the compounds described in EP 627406 A1, for example the compound of formula I

in which R ₁ denotes a straight or branched (C ₁₂ -C ₂₂ ) carbon chain,

- wherein said chain can carry a bond or a heteroatom selected from a double bond, a triple bond, O, S, NR ₆ , where R ₆ is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and / or

- may have, as a substituent, an alkoxy group, an alkenyloxy group, an alkynyloxy group, an aralkyloxy group, an acyl group, an alkylamino group, an alkylthio group, an acylamino group, an alkoxycarbonyl group, an alkoxycarbonylamino group, an acyloxy group, a hydrocarbylhydroxy-hydroxy, nitroxy-hydroxy, nitro-hydroxy, nitro-hydroxy, nitro-hydroxy, nitro-hydroxy, nitro, hydroxy-hydroxy, nitro group, hydroxy, hydroxy, nitro group, hydroxy, hydroxy, nitro group, hydroxy, hydroxy, nitro groups or

R ₁ is

- phenylalkyl, in which alkyl denotes a straight or branched (C ₆ -C ₂₀ ) carbon chain; or

- phenylalkyl in which alkyl is a straight or branched (C ₁ -C ₃₀ ) carbon chain, where phenylalkyl is substituted

a straight or branched (C ₆ -C20) carbon chain optionally substituted with halogen,

A C ₆ -C ₂₀ alkoxy group of a straight or branched chain, optionally substituted with halogen,

- C ₆ -C ₂₀ alkenyloxy straight or branched chain,

a phenylalkoxy group, a halophenylalkoxy group, a phenylalkoxyalkyl, a phenoxyalkoxy group or a phenoxyalkyl,

cycloalkyl substituted with C ₆ -C ₂₀ alkyl,

heteroarylalkyl substituted with C ₆ -C ₂₀ alkyl,

heterocyclic C ₆ -C ₂₀ alkyl, or

heterocyclic alkyl substituted with C ₆ -C ₂₀ alkyl,

and where

alkyl group may carry

- in the carbon chain, a bond or heteroatom selected from a double bond, a triple bond. O, S, sulfinyl, sulfonyl or NR ₆ , where R ₆ has the above meanings, and

- as a substituent, an alkoxy group, an alkenyloxy group, an alkynyloxy group, an aralkyloxy group, an acyl group, an alkylamino group, an alkylthio group, an acylamino group, an alkoxycarbonyl group, an alkoxycarbonylamino group, an acyloxy group, an alkylcarbamoyloxyhydroxy, nitroxy, nitroxy, nitroxy, nitrocarbon, hydroxy, nitro, hydroxy, nitro, hydroxy group and

R ₂ , R ₃ , R ₄ and R ₅ each independently of one another are H, C ₁ -C ₄ alkyl or acyl,

or a pharmaceutically acceptable salt thereof;

- the compounds described in EP 1002792 A1, for example the compound of formula II

in which m represents 1-9 and R ' ₂ , R' ₃ , R ' ₄ and R' ₅ each independently from each other represents H, alkyl or acyl,

or a pharmaceutically acceptable salt thereof;

- the compounds described in EP 0778263 A1, for example the compound of formula III

in which W is H; C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl; phenyl unsubstituted or substituted by an OH group; R _{4 4} O (CH ₂ ) n; or C ₁ -C ₆ alkyl substituted with 1-3 substituents selected from the group consisting of halogen, C ₃ -C ₈ cycloalkyl, phenyl and phenyl substituted with OH;

X is H or unsubstituted or substituted straight chain alkyl bearing p carbon atoms, or an unsubstituted or substituted straight chain alkoxy group carrying (p-1) carbon atoms, for example, substituted by 1-3 substituents selected from the group consisting of C ₁ - C ₆ alkyl, OH, C ₁ -C ₆ alkoxy group, acyloxy group, amino group, C ₁ -C ₆ alkylamino group, acylamino group, oxo group, halo C ₁ -C ₆ alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₆ alkyl, OH, C ₁ -C ₆ alkoxy, acyl, atsiloksigrup y, amino, C ₁ -C ₆ alkylamino group, an acylamino group, a halo _C1-C6 alkyl and halogen; Y is H, C ₁ -C ₆ alkyl, OH, C ₁ -C ₆ alkoxy group, acyl, acyloxy group, amino group, C ₁ -C ₆ alkylamino group, acylamino group, haloC ₁ -C ₆ alkyl or halogen; Z ₂ denotes a single bond or straight chain alkylene bearing q carbon atoms,

where p and q are each independently an integer from 1 to 20, provided that 6≤p + q≤23, m 'is 1, 2 or 3, n is 2 or 3, R'' ₁ , R'' ₂ , R'' ₃ and R'' ₄ each independently of one another is H, C ₁ -C ₄ alkyl or acyl,

or a pharmaceutically acceptable salt thereof;

- the compounds described in WO 02/18395, for example the compound of formula IVa or IVb

или

or

in which X _a is O, S, NRis or a group - (CH ₂ ) _na -, where the group is unsubstituted or is substituted by 1-4 halogen atoms; n _a is 1 or 2, R _1s is H or C ₁ -C ₄ alkyl, where alkyl is unsubstituted or substituted with halogen; R _1a is H, OH, C ₁ -C ₄ alkyl or O (C ₁ -C ₄ ) alkyl, where the alkyl is unsubstituted or is substituted with 1-3 halogen atoms; R _1b is H, OH or (C ₁ -C ₄₎ -alkyl, wherein alkyl is unsubstituted or substituted by halogen;

R _2a each independently selected from H or C ₁ -C ₄ alkyl, where the alkyl is unsubstituted or substituted by halogen; R _3a is H, OH, halogen or O (C ₁ -C ₄ ) alkyl, where alkyl is unsubstituted or substituted with halogen; and R _3b is H, OH, halogen, C ₁ -C ₄ alkyl, where alkyl is unsubstituted or substituted with hydroxy, or O (C ₁ -C ₄ ) alkyl, where alkyl is unsubstituted or substituted with halogen; Y _a is —CH ₂ -, —C (O) -, —CH (OH) -, —C (= NOH) -, O or S, and R _4a is C ₄ -C ₁₄ alkyl or C ₄ -C ₁₄ alkenyl;

or a pharmaceutically acceptable salt or hydrate thereof;

- compounds described in WO 02/076995, for example a compound of formula V

wherein

m _c is 1, 2 or 3;

_And X is O or a direct bond;

R _1c is H, C ₁ -C ₆ alkyl optionally substituted with OH, acyl, halogen, C ₃ -C ₁₀ cycloalkyl, phenyl or hydroxyphenylene; C ₃ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; or phenyl optionally substituted with OH;

R _2c is

in which R _5c is H, C ₁ -C ₄ alkyl optionally substituted with 1, 2 or 3 halogen atoms, and R _6c is H or C ₁ -C ₄ alkyl optionally substituted with halogen;

R _3c and R _{4c are} each independently H, C ₁ -C ₄ alkyl optionally substituted with halogen, or acyl, and

R _c is C ₁₃ -C ₂₀ alkyl, which optionally may carry an oxygen atom in the chain and which may optionally be substituted with a nitro group,

halogen, amino, hydroxy or carboxy; or a group of formula (a)

wherein R _7c is H, C ₁ -C ₄ alkyl or a C ₁ -C ₄ alkoxy group, and R _8c is a substituted C ₁ -C ₂₀ alkanoyl, phenylC ₁ -C ₁₄ alkyl, where C ₁ -C ₁₄ alkyl is optionally substituted with halogen or OH, a cycloalkylC ₁ -C ₁₄ alkoxy group or phenylC ₁ -C ₁₄ alkoxy group, where the cycloalkyl or phenyl ring is optionally substituted with halogen, C ₁ -C ₄ alkyl and / or C ₁ -C ₄ alkoxy group, phenyl C ₁ -C ₁₄ alkoxyC ₁ - C ₁₄ alkyl,

phenoxyC ₁ -C ₁₄ alkoxy group or phenoxyC ₁ -C ₁₄ alkyl,

R _c also denotes a group of formula (a) in which R _8c is a C ₁ -C ₁₄ alkoxy group when R _1c is C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl,

or a compound of formula VI

wherein

n _x is 2, 3 or 4

R _1x is H, C ₁ -C ₆ alkyl optionally substituted with OH, acyl, halogen, cycloalkyl, phenyl or hydroxyphenylene; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; or phenyl optionally substituted with OH;

R _2x is H; C ₁ -C ₄ alkyl or acyl

R _3x and R _{4x are} each independently H, C ₁ -C ₄ alkyl optionally substituted with halogen or acyl,

R _5x is H, C ₁ -C ₄ alkyl or a C ₁ -C ₄ alkoxy group, and

R _6x is C ₁ -C ₂₀ alkanoyl substituted with cycloalkyl; cycloalkylC ₁ -C ₁₄ alkoxy group, where the cycloalkyl ring is optionally substituted with halogen, C ₁ -C ₄ alkyl and / or C ₁ -C ₄ alkoxy group; phenylC ₁ -C ₁₄ alkoxy group, where the phenyl ring is optionally substituted with halogen, C ₁ -C ₄ alkyl and / or C ₁ -C ₄ alkoxy group,

R _6x may also denote a C ₄ -C ₁₄ alkoxy group when R _1x is C ₂ -C ₄ alkyl substituted with OH, or a pentyloxy group or hexyloxy group when R _1x is C ₁ -C ₄ alkyl,

with the proviso that R _6x does not denote a phenylbutyleneoxy group when either R _5x is H or R _1x is methyl, or a pharmaceutically acceptable salt thereof.

- the compounds described in WO 02/06268 A1, for example the compound of formula VII

in which R _1d and R _2d each independently from each other represents H or an amino protecting group;

R _3d is hydrogen, a hydroxy protecting group or a group of the formula

R _4d is lower alkyl;

n _d is an integer from 1 to 6;

X _d is ethylene, vinylene, ethynylene, a group of the formula —D — CH ₂ - (in which D is carbonyl, —CH (OH) -, O, S or N), aryl or aryl having up to three substituents selected from the following group a;

Y _d is a single bond, C ₁ -C ₁₀ alkylene, C ₁ -C ₁₀ alkylene having up to three substituents selected from groups a and b, C ₁ -C ₁₀ alkylene bearing O or S in the middle or at the end of the carbon chains, or C ₁ -C ₁₀ alkylene, bearing O or S in the middle or at the end of the carbon chain, which has up to three substituents selected from groups a and b;

R _5d is hydrogen, cycloalkyl, aryl, heterocycle, cycloalkyl having up to three substituents selected from groups a and b, aryl having up to three substituents selected from groups a and b, or heterocycle having up to three substituents, selected from groups a and b;

R _6d and R _7d each independently from each other denotes H or a Deputy selected from group a;

R _6d and R _9d each independently from each other denotes H or

C ₁ -C ₄ alkyl optionally substituted with halogen;

"Group a" includes halogen, (ness.) Alkyl, halogen (ness.) Alkyl, (ness.) Alkoxy group, (ness.) Alkylthio group, carboxyl, (ness.) Alkoxycarbonyl, hydroxy group, aliphatic (ness.) Acyl, amino group mono (ness.) alkylamino group, di (ness.) alkylamino group, aliphatic (ness.) acylamino group, cyano group or nitro group; and “group b” includes cycloalkyl, aryl, heterocycle, each of which optionally has up to three substituents selected from group a; with the proviso that when R _5d is hydrogen, Y _{d is} not a single bond and a linear C ₁ -C ₁₀ alkylene, or a pharmacologically acceptable salt or ester thereof;

- the compounds described in JP-14316985 (JP 2002316985), for example the compound of formula VIII

in which R _1e , R _2e , R _3e , R _4e , R _5e , R _6e , R _7e , n _e , X _e, and Y _e are as defined in JP-14316985;

or a pharmacologically acceptable salt or ester thereof;

- the compounds described in WO 03/29184 and WO 03/29205, for example a compound of formula IX

wherein

X _f is O or S and R _1f, R _2f, R _3f and n _f are as defined in WO 03/29184 and WO 03/29205,

R _4f and R _5f each independently from each other denotes H or a group of the formula

in which R _8f and R _9f each independently of one another is H or C ₁ -C ₄ alkyl optionally substituted with halogen; for example 2-amino-2- [4- (3-benzyloxyphenoxy) -2-chlorophenyl] propyl-1,3-propanediol or 2-amino-2- [4- (benzyloxyphenylthio) -2-chlorophenyl] propyl-1,3 -propanediol, or its pharmacological salt.

- the compounds described in WO 03/062252 A1, for example the compound of formula X

wherein

Ar is phenyl or naphthyl; mg and ng are each independently 0 or 1; A is selected from COOH, PO ₃ H ₂ , PO ₂ H, SO ₃ H, PO (C ₁ -C ₃ alkyl) OH and 1H-tetrazol-5-yl; R _1g and R _{2g are} each independently H, halogen, OH, COOH or C ₁ -C ₄ alkyl optionally substituted with halogen; R _3g is H or C ₁ -C ₄ alkyl optionally substituted with halogen or OH; R _4g each independently of one another is halogen or optionally substituted with halogen C ₁ -C ₄ alkyl or C ₁ -C ₃ alkoxy group; and R _g and M have one of the meanings indicated for B and C, respectively, in WO 03/062252 A1;

- the compounds described in WO 03/062248 A2, for example the compound of formula XI

wherein

Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH, 1H-tetrazol-5-yl, PO ₃ H _2, PO ₂ H _2, -SO ₃ H or PO (R _5h) OH, where R _5h is selected from C ₁ -C ₄ alkyl, hydroxyC ₁ -C ₄ alkyl, phenyl, —CO — C ₁ –C ₃ alkoxy groups and —CH (OH) phenyl, where the phenyl or phenyl group is optionally substituted; R _1h and R _{2h are} each independently H, halogen, OH, COOH or optionally halogen-substituted C ₁ -C ₆ alkyl or phenyl; R _3h is H or C ₁ -C ₄ alkyl optionally substituted with halogen and / or OH; R _4h each independently of one another is halogen, OH, COOH, C ₁ -C ₄ alkyl,

S (O) (C ₁ -C ₃ ) _{0,2 or 3} alkyl, C ₁ -C ₃ alkoxy group, C ₃ -C ₆ cycloalkoxy group, aryl or aralkoxy group, where aryl groups may optionally be substituted with 1-3 halogen atoms; and R _g and M each have one of the meanings indicated for B and C, respectively, in WO 03/062248 A2.

According to a further embodiment of the invention, the S1P receptor agonist that is used in the combination of the present invention may also be a compound having a selective effect on the S1P1 receptor, for example, a compound whose action on the S1P1 receptor is superior to its action on the S1P3 receptor by at least 20 times, for example 100, 500, 1000 or 2000 times, which was estimated based on the ratio of the EC ₅₀ values for the S1P1 receptor and the EC ₅₀ values for the S1P3 receptor, obtained using binding assay GTFγS 358, the EC ₅₀ value of said compound upon binding to the S1P1 receptor was about 100 nM or less according to the binding assay, 358 GTFγS. Representative S1P1 receptor agonists are, for example, the compounds listed in WO 03/061567, the contents of which are incorporated herein by reference, for example, a compound of the formula

or

In each case, when reference is made to patent applications, it is understood that thereby their essence regarding the compounds is incorporated into this description by reference.

Acyl may be a group R _y -CO-, wherein R _y represents C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl or phenylC ₁ -C ₄ alkyl. Unless otherwise indicated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.

When in the compounds of formula I the carbon chain representing R ₁ is substituted, it is preferably substituted with a halogen, nitro group, amino group, hydroxy group or carboxy group. When the carbon chain carries optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene group is substituted, it is preferably substituted with a halogen, nitro group, amino group, methoxy group, hydroxy group or carboxy group.

Preferred compounds of formula I are compounds in which R ₁ is C ₁₃ -C ₂₀ alkyl optionally substituted with a nitro group, halogen, amino group, hydroxy group or carboxy group, and more preferably compounds in which R ₁ is phenylalkyl substituted with C ₆ -C ₁₄ alkyl a chain optionally substituted with halogen, and the alkyl group is C ₁ -C ₆ alkyl optionally substituted with a hydroxy group. More preferably, R ₁ is phenylC ₁ -C ₆ alkyl substituted on the phenyl group with a straight or branched, preferably straight C ₆ -C ₁₄ alkyl chain. The C ₆ -C ₁₄ alkyl chain may be in the ortho, meta, or para position, preferably in the para position.

Preferably R ₂ -R ₅ each is N.

A preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propanediol. The most preferred S1P receptor agonist of formula I is FTY720, i.e. 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol in free form or in the form of a pharmaceutically acceptable salt (hereinafter referred to as compound A), for example, in the form of the hydrochloride of the following formula

A preferred compound of formula II is a compound in which R _'2 -R' ₅ each are H and m is 4, i.e., 2-amino-2- {2- [4- (1-oxo-5-phenylpentyl) phenyl] ethyl} propane-1,3-diol, in free form or in the form of its pharmaceutically acceptable salt (hereinafter referred to as compound B), for example in the form of a hydrochloride.

A preferred compound of formula III is a compound in which W is CH ₃ , R ″ _1- R ″ 3 each is H, Z ₂ is ethylene, X is heptyloxy and Y is H, i.e. 2-amino-4- (4-heptyloxyphenyl) -2-methylbutanol, in free form or in the form of its pharmaceutically acceptable salt (hereinafter referred to as compound B), for example in the form of a hydrochloride. Most preferred is the R-enantiomer.

A preferred compound of formula IVa is PTY720-phosphate (R _2a is H, R _3a is OH, X _a is O, R _1a and R _1b are OH). A preferred compound of formula IVb is the phosphate of compound B (R _2a is H, R _3b is OH, X _a is O, R _1a and R _1b is OH, Y _a is O and R _4a is heptyl). A preferred compound of formula V is the phosphate of compound B.

A preferred compound of formula V is mono [(R) -2-amino-2-methyl-4- (4-pentyloxyphenyl) butyl] phosphoric acid ester.

A preferred compound of formula VIII is (2R) -2-amino-4- [3- (4-cyclohexyloxybutyl) benzo [b] thien-6-yl] -2-methylbutan-1-ol.

When the compounds of formulas I-XIII have one or more asymmetric centers in the molecule, various optical isomers, as well as racemates, diastereoisomers and mixtures thereof, fall within the scope of the invention.

Examples of pharmaceutically acceptable salts of the compounds of formulas I-XIII include salts with inorganic acids such as hydrochloride, hydrobromide and sulfate, salts with organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate, or optionally salts with metals such as sodium, potassium, calcium and aluminum, salts with amines such as triethylamine, and salts with dibasic amino acids such as lysine. Formulations in the form of hydrates and solvates fall within the scope of the compounds and salts of the present invention.

S1P receptor binding can be evaluated using the following assay methods.

A. Affinity for binding of S1P receptor agonists to individual human S1P receptors.

Short-term transfection of HEK293 cell line with human S1P receptors

S1P receptors and G1 proteins were cloned, equal amounts of four cDNAs encoding the EDG, G _i -α, G _i -β and G _i -γ receptor were mixed, and used for transfection of HEK293 cell monolayers by precipitation with calcium phosphate (M. Wigler and et al., Cell., 11, 1977, p. 223 and DS Im et al., Mol. Pharmacol., 57, 2000, p. 753). In general, the method was as follows. DNA mixture containing 25 ug of DNA and 0.25 M CACL ₂ was added to HEPES, buffered 2 mM Na ₂ HPO _4. 25 mM chloroquine was added to subconfluent monolayers of HEK293 cells and then a DNA pellet was added to the cells. After 4 hours, the monolayers were washed with phosphate-buffered saline and fed with media (90% of the mixture (1: 1) Dulbecco's modified Eagle's medium (DMEM): F-12 + 10% fetal bovine serum). Cells were harvested 48-72 hours after the addition of DNA by scraping into NME buffer (20 mM HEPES, 5 mM MgCl ₂ , 1 mM EDTA, pH 7.4) containing 10% ice-cold sucrose, and was destroyed using a Dounce homogenizer. After centrifugation at 800 × g, the supernatant was diluted with HME without adding sucrose and centrifuged at 100,000 × g for 1 h. The resulting debris was re-homogenized and centrifuged at 100,000 × g for another hour. The resulting crude debris of the membranes was resuspended in NME with the addition of sucrose, aliquoted, and instantly frozen by immersion in liquid nitrogen. Membranes were stored at -70 ° C. Protein concentration was determined spectroscopically using protein analysis according to the Bradford method.

GTPγS Binding Assay Using S1P / HEK293 Receptor Membrane Preparations

GTPγS binding assays were performed according to the method described by DSIm et al., Mol. Pharmacol., 57, 2000, p. 753. Ligand-mediated GTPγS binding to G proteins was evaluated in GTP binding buffer (50 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ , pH 7.5) using 25 μg of membrane preparation obtained from transiently transfected HEK293 cells. The ligand was added to the membranes in the presence of 10 μM HDF and

0.1 nM [ ³⁵ S] GTPγS (1200 Ci / mmol) and incubated at 30 ° C for 30 minutes. Bound GTPγS was separated from a Brandel unbound Harvester (Gaithersburg, Maryland) and counted using a liquid scintillation counter.

The composition of the invention preferably contains from 0.01 to 20% by weight of S1P receptor agonists, more preferably from 0.1 to 10% by weight, for example from 0.5 to 5% by weight, based on the weight of the whole composition.

Sugar alcohol can act as a diluent, carrier, filler or agent to increase the volume and it is convenient to use mannitol, maltitol, inositol, xylitol or lactitol, preferably practically non-hygroscopic sugar alcohol, for example mannitol (D-mannitol). You can use sugar alcohol individually or use a mixture of two or more sugar alcohols, for example a mixture of mannitol and xylitol, for example in a ratio of from 1: 1 to 4: 1.

In a most preferred embodiment, sugar alcohol is prepared from a spray dried composition, for example a mannitol composition, which has a large specific surface area. The use of this type of mannitol composition can help to ensure uniform distribution of the S1P receptor agonist in mannitol in the composition. A large surface area can be obtained by creating a sugar alcohol preparation, for example mannitol, consisting of particles that have a smaller average size and / or a rougher surface for each particle. It has also been found that the use of spray dried sugar alcohol, for example mannitol, with an average particle size of 300 μm or less, can improve the compressibility and hardness of tablets made from the composition.

Preferably, the specific surface area of one particle of a sugar alcohol preparation, for example mannitol, is from 1 to 7, for example from 2 to 6, or from 3 to 5 m ² / g. A suitable preparation of mannitol may have an average particle size of from 100 to 300, for example from 150 to 250 microns, and a bulk density of from 0.4 to 0.6, for example from 0.45 to 0.55 g / ml. A suitable large surface area mannitol is Parteck M200, available from E. Merck.

The composition preferably contains from 75 to 99.99 wt.% Sugar alcohol, more preferably from 85 to 99.9, for example from 90 to 99.5 wt.%, Based on the weight of the whole composition.

The composition preferably also contains a sizing. Suitable lubricants are stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, canola oil, hydrogenated vegetable oil such as hydrogenated castor oil (e.g. Cutina® or Lubriwax® sodium magnesium, mineral oil, mineral oil, mineral oil), colloidal silicon dioxide, organosilicon liquid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer or a mixture of any of the above substances. Preferably, the sizing is magnesium stearate, hydrogenated castor oil or mineral oil. Less preferred as a sizing agent are colloidal silicon dioxide and polyethylene glycol.

The composition preferably contains from 0.01 to 5 wt.% Sizing, more preferably from 1 to 3, for example about 2 wt.%, Based on the weight of the whole composition.

The composition may contain one or more other excipients, such as carriers, binders or diluents. In particular, the composition may comprise microcrystalline cellulose (e.g. Avicel®), methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch (e.g. corn starch) or dicalcium phosphate, preferably in an amount of from 0.1 to 90, for example from 1 to 30% by weight, based on on the mass of the whole composition. If a binder is used, for example microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, it is preferably included in an amount of from 1 to 8, for example from 3 to 6 wt.%, Based on the weight of the whole composition. The use of a binder increases the strength of the granules of the drug, which is very important for thin granules. Microcrystalline cellulose and methyl cellulose are most preferably used when high tablet hardness and / or longer disintegration times are required. Hydroxypropyl cellulose is preferably used when faster disintegration is required. If necessary, xylitol can also be added as an additional binder, for example, in addition to microcrystalline cellulose, for example in an amount up to 20 wt.% In terms of sugar alcohol, for example xylitol.

In one embodiment, the composition further comprises a stabilizer, preferably glycine-HCl or sodium bicarbonate. The stabilizer may be present in an amount of, for example, from 0.1 to 30, preferably from 1 to 20 wt.%.

The composition may be in the form of a powder, granules or pellets, or in unit dosage form, for example, in the form of a tablet or capsule. The compositions of the present invention are well adapted for encapsulation in a shell intended for oral administration of a capsule, especially in a hard gelatin shell.

Alternatively, the compositions may be compressed into tablets. The tablets can optionally be coated, for example, with talc or polysaccharide (e.g., cellulose), or a coating of hydroxypropyl methylcellulose.

If the pharmaceutical capsule is a unit dose, it is convenient that each unit dose contains from 0.5 to 10 mg of an S1P receptor agonist.

The compositions of the invention can have good stability characteristics, as demonstrated by standard stability tests, for example, they remain stable during storage for up to one, two or three years, or even longer. The stability characteristics can be determined, for example, by evaluating the decomposition products using HPLC analysis after storage for specific periods of time at specific temperatures, for example, at 20, 40 or 60 ° C.

The pharmaceutical compositions of the present invention can be prepared by standard methods, for example using conventional methods of mixing, granulation, sugar coating, dissolution or lyophilization. Procedures that can be used for this are known in the art, for example, they are described by L. Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd ed., 1986, H. Sucker et al., Pharmazeutische Technology, Thieme, 1991; Hagers Handbuch der pharmazeutischen Praxis, 4th, Springer, 1971; and Remington's Pharmaceutical Sciences, 13th, Mack Publ. Co., 1970 or later.

One of the objects of the present invention is a method for producing a pharmaceutical composition, which consists in the fact that

(a) mixing an S1P receptor agonist with sugar alcohol;

(b) grinding and / or granulating the mixture obtained in stage (a); and

(c) mixing the milled and / or granular mixture obtained in step (b) with a sizing agent.

Using this method, preparations are obtained having a high level of content and uniformity of the mixture (i.e., an almost uniform distribution of the S1P receptor agonist in the composition), the required dissolution time and stability.

Prior to step (a), an S1P receptor agonist, i.e. 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride, optionally, can be finely ground and / or pre-sieved through a sieve with a mesh size of 400 to 500 μm to remove lumps. The mixing step (a) can be carried out by mixing the S1P receptor agonist and a sugar alcohol, for example mannitol, in any suitable mixer or mixer for, for example, 100-400 revolutions.

The method can be carried out by dry mixing the components. In this embodiment, in the mixing step (b), the mixture obtained in step (a) can be passed through a sieve, preferably having a hole size of 400 to 500 μm. In step (a) of the method, it is possible to carry out the step of mixing the entire amount of the S1P receptor agonist first with a small amount of sugar alcohol, comprising, for example, from 5 to 25 wt.% Of the total weight of sugar alcohol, to prepare the premix. Then the rest of the sugar alcohol is added to the premix. Step (a) may also include the step of adding to the mixture a solution of a binder, for example methyl cellulose and / or xylitol, for example in the form of an aqueous solution. Alternatively, the binder is added to the mixture dry and water is added at the granulation stage.

The milled mixture obtained in step (b) can optionally be mixed again before mixing with a sizing agent. Before mixing, a sizing agent, for example magnesium stearate, is preferably sieved, for example, through a sieve with a hole size of from 800 to 900 microns.

Alternatively, the wet granulation method is used. In this embodiment, the S1P receptor agonist is preferably first dry mixed with the desired sugar alcohol, for example mannitol, and then the resulting sugar alcohol / S1P receptor agonist mixture is dry mixed with a binder, such as hydroxypropyl cellulose or hydroxypropyl methyl cellulose. Water is then added and the mixture is granulated, for example using an automatic granulator. Then the granulate is dried and ground.

If necessary, in step (c), an additional amount of a binder can be added to the mixture obtained in step (b).

The method may include an additional step of tabletting or encapsulating the mixture obtained in step (c), for example, in a hard gelatin capsule using an automatic encapsulating device. Capsules can be colored or labeled to give an individual look and for quick recognition. The use of dyes can serve both to improve the appearance and to identify capsules. Dyes suitable for pharmaceutical use typically include carotenoids, iron oxides, and chlorophyll. Preferably, the capsules of the invention are labeled using a code.

The pharmaceutical compositions of the present invention can be used either individually or in combination with other active ingredients for the treatment and prevention of conditions such as those described in US 5604229, WO 97/24112, WO 01/01978, US 6004565, US 6274629 and JP- 14316985, the contents of which are incorporated into this description by reference.

Pharmaceutical compositions can be used primarily for

a) treating and preventing organ or tissue transplant rejection, for example, for treating recipients of heart transplants, lungs, combined heart-lung transplants, liver, kidneys, pancreas, skin or cornea, and to prevent the transplant against the host, which sometimes occurs after bone marrow transplantation; primarily for the treatment of acute or chronic rejection of an allo- and xenograft or for transplantation of insulin-producing cells, for example, islet cells of the pancreas;

b) treating and preventing autoimmune disease or inflammatory conditions, such as multiple sclerosis, arthritis (e.g. rheumatoid arthritis), inflammatory bowel disease, hepatitis, etc.

c) treatment and prevention of viral myocarditis and viral diseases associated with viral myocarditis, including hepatitis and AIDS.

Therefore, the following objects of the present invention are the following

1. The above composition is intended for the treatment or prevention of the above disease or condition.

2. A method of treating an individual in need of immunomodulation, which method comprises administering to the individual an effective amount of the above composition.

3. A method of treating or preventing the aforementioned disease or condition, the method comprising administering the above composition to an individual.

4. The use of the above pharmaceutical composition for the preparation of a medicament for the prevention or treatment of the above disease or condition.

The invention is described below with reference to the following specific embodiments of the invention.

Example 1

Fine-grained compound A, for example, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride (FTY720) is sieved through a sieve and 116.7 g of the sifted compound are mixed with 9683.3 g of mannitol ( Parteck M200, E. Merck). The mixture is then milled in a Frewitt MGI type apparatus (Key International Inc. USA) using a 30 mesh sieve. Magnesium stearate is sieved through a 20 mesh sieve. and 200 g of the sieved compound are mixed with the FTY720 / mannitol mixture to give a product composition.

Then the composition of the product is compressed using a tablet press using a 7 mm punch to obtain tablets weighing 120 mg, each of which contains:

Compound A, e.g. FTY720 * 1.4 mg Mannitol M200 116.2 mg Magnesium stearate 2.4 mg Total 120 mg * 1 mg of compound A in free form is equivalent to 1.12 mg of FTY720

Example 2

The following example repeats the process described in example 1, except that Cutina® (hydrogenated castor oil) is used instead of magnesium stearate.

Example 3

Compound A, for example FTY720, and mannitol (Parteck M200, E. Merck) are each individually sieved through an 18 mesh sieve. 1.9 g sieved FTY720 is mixed with 40 g sieved mannitol in a blender at 32 rpm for 120 revolutions. The PTY720 / mannitol mixture is then sieved through a 35 mesh sieve.

The sieved FTY720 / mannitol mixture is added to the granulator together with another 340.1 g of mannitol and 12 g of hydroxypropyl cellulose. The mixture is stirred for 3 minutes. Water is then added at a rate of 100 ml / min and the mixture is granulated for 2 minutes. The granulate was transferred to a tray dryer and dried at 50 ° C for 150 minutes.

The mixture is then milled in a Frewitt MGI type apparatus using a 35 mesh sieve. Magnesium stearate is sieved and 6 g of the sieved compound are mixed for 90 revolutions at 32 rpm with an FTY720 / mannitol mixture to give a product composition having a substantially uniform distribution of the S1P receptor agonist in the mannitol in the mixture.

Then, the size 3 solid gelatin shells are filled with a Hoflinger & Karg 400 encapsulating device using a product composition. 120 mg of the product composition is added to each capsule.

Thus, each capsule contains:

FTY720 * 0.56 mg Mannitol M200 114.04 mg Hydroxypropyl cellulose 3.6 mg Magnesium stearate 1.8 mg Total 120 mg

Example 4

In the following example, the process described in example 3 is repeated, except that Cutina® (hydrogenated castor oil) is used instead of magnesium stearate.

Example 5

In the following example, the process described in example 3 is repeated, except that instead of hydroxypropyl cellulose, hydroxypropyl methyl cellulose is used.

Example 6a

Fine compound A, for example FTY720, is sieved using a sieve with a mesh size of 400 μm (40 mesh). 58.35 g of the screened compound are mixed with 4841.65 g of mannitol (Parteck M200, E. Merck) in a 25 liter Bohle hopper mixer for 240 revolutions. The mixture is then milled in a Frewitt MGI type apparatus using a sieve with an opening size of 400 μm and the milled mixture is mixed once more. Magnesium stearate is sieved and 100 g of the sifted product is mixed with a PTY720 / mannitol mixture to obtain a product composition having a substantially uniform distribution of the S1P receptor agonist in mannitol in the mixture.

Then, the size 3 solid gelatin shells are filled with a Hoflinger & Karg 400 encapsulating device using a product composition. 120 mg of the product composition is added to each capsule. Thus, each capsule contains:

FTY720 * 1.4 mg Mannitol M200 116.2 mg Magnesium stearate 2.4 mg Total 120 mg

Example 6b

In an alternative embodiment of the invention, the capsules are made using the components and their amounts indicated in Example 6a, but first FTY720 is mixed with 14 mg of mannitol (before sieving). Then the mixture is sieved as described above. After this, the sifted mixture is mixed with the remaining part of mannitol and magnesium stearate is added, after which additional mixing and filling of the capsules is carried out.

Examples 7 and 8

In the following examples, capsules are prepared according to the method described in example 6, except that each capsule contains the following amounts of each component:

Example 7 Example 8 FTY720 * 2.8 mg 5.6 mg Mannitol M200 114.8 mg 112 mg Magnesium stearate 2.4 mg 2.4 mg Total 120 mg 120 mg

Examples 9-11

In the following examples, capsules were prepared according to the method described in examples 6-8, except that in each case the magnesium stearate was replaced with Cutina® (hydrogenated castor oil).

Examples 12-22

In the following examples, capsules or tablets are prepared according to the method described in examples 1-11, except that in each case 2-amino-2- {2- [4- (1-oxo-5-phenylpentyl) hydrochloride is used instead of FTY720 phenyl] ethyl} propane-1,3-diol.

Examples 23 and 24

Capsules containing the following ingredients are prepared by weighing each component and mixing in a mortar, after which the capsules are filled with a mixture:

Example 23 Example 24 FTY720 5 mg 1 mg D-mannitol 83.7 mg 117 mg Corn starch 24 mg - Avicel® PPH101 12 mg - Hydroxypropyl cellulose 0.3 mg 7 mg Talc 3 mg 3 mg Lubri wax® 101 2 mg 2 mg Total 130 mg 130 mg

Examples 25-27

Pharmaceutical compositions are prepared containing the following ingredients:

Example 25 Example 26 Example 27

FTY720 5 g 10 g 100 g D-mannitol 991 g 986 g 897 g Cellulose SM-25 4 g 4 g 3 g Total 1000 g 1000 g 1000 g

FTY720 and a part of D-mannitol, the mass of which is equal to two masses of FTY720, are mixed in a mixer of the type Microspeed Mixer MS-5 (Palmer, USA) for 2 minutes at 1200 rpm. The remainder of D-mannitol is added to the mixture and mixed for another 2 minutes. From the hopper, 80 or 60 ml of a 5% solution of SM-25 methylcellulose solution are added and granulated under the same conditions. The mixture is extruded through a sieve with a hole size of 0.4 mm using an extruder type RG-5. The extruded product was dried at 65 ° C. in a STREA I fluidized bed granulator (Patheon, Canada) and then sieved through a 24 mesh sieve. Fine particles passing through a 60 mesh sieve are removed. The resulting small granules are filled into capsules using a Zuma capsule filling machine (100 mg per capsule).

Examples 28-31

Get tablets containing the following ingredients (in mg):

Example 28 Example 29 Example 30 Example 31 FTY720 one one one one D-mannitol 62.3 62.3 62.0 62.0 Xylitol * 26.7 (5.4) 26.7 (5.4) 26.6 26.6 Cellulose - - 0.4 0.4 Microcrystalline cellulose 24.0 - 24.0 - Low Substituted Hydroxypropyl Cellulose - 24.0 - 24.0 Hydrogenated oil 6.0 6.0 6.0 6.0 Total 120.0 120.0 120.0 120.0 * the amount of xylitol indicated in parentheses is used as a binder

FTY720, D-mannitol and xylitol are introduced into a fluidized bed granulator (model MP-01, Powrex), mixed for 5 min and granulated in a sprayed binder solution, and then dried until the outlet temperature reaches 40 ° C. Granulation conditions are given below. The dried powder is passed through a 24 mesh sieve, added to a certain amount of filler and sizing and mixed in a mixer (Tubular Mixer, WAB) for three minutes to obtain a powder intended for pressing.

The resulting powder is compressed using a tabletting machine (type Cleanpress correct 12 HUK, Kikushui Seasakusho firm) using a 7 mm punch (inner diameter) × 7.5 mm R with a compression force of 9800 N.

Granulation conditions:

Parameter adjustment parameter Loading quantity 1170 g Intake air volume 50 m ³ / min Intake air temperature 75 ° C Spray rate 15 ml / min Atomized air pressure 15 N / cm ² Air Volume 30 l / min Binder Solution Volume 351 ml

Examples 32-39

Get tablets containing the following ingredients (in mg):

Claims (18)

1. Solid pharmaceutical composition suitable for oral administration, which contains
(a) an S1P receptor agonist; and
(b) sugar alcohol,
in which the S1P receptor agonist is selected from
compounds of formula I

in which R ₁ denotes a straight or branched (C ₁₂ -C ₂₂ ) carbon chain,
wherein said chain can carry a bond or heteroatom selected from a double bond, a triple bond, O, S, NR ₆ , where R ₆ is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and / or
may have as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or R ₁ is
phenylalkyl in which alkyl represents a straight or branched (C ₆ -C ₂₀ ) carbon chain; or
phenylalkyl in which alkyl denotes a straight or branched (C ₁ -C ₃₀ ) carbon chain, where phenylalkyl is substituted
straight or branched (C ₆ -C ₂₀ ) carbon chain optionally substituted with halogen,
C ₆ -C ₂₀ alkoxy group with a straight or branched chain, optionally substituted with halogen,
C ₆ -C ₂₀ alkenyloxy straight or branched chain,
phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, cycloalkyl, substituted C ₆ -C ₂₀ alkyl,
heteroarylalkyl substituted with C ₆ -C ₂₀ alkyl,
heterocyclic C ₆ -C ₂₀ alkyl, or
heterocyclic alkyl substituted with C ₆ -C ₂₀ alkyl, and where the alkyl group may carry
in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR ₆ where R ₆ is as defined above, and
as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy or carboxy; R ₂ , R ₃ , R ₄ and R ₅ each independently of one another are H, C ₁ -C ₄ alkyl or acyl, or a pharmaceutically acceptable salt thereof. 2. The composition of claim 1, wherein the S1P receptor agonist is selected from 2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol or a pharmaceutically acceptable salt thereof. 3. The composition according to claim 2, in which the salt is hydrochloride. 4. The composition according to one of claims 1 to 3, in which the sugar alcohol is a non-hygroscopic sugar alcohol or mixtures thereof. 5. The composition according to claim 4, in which the sugar alcohol is mannitol. 6. The composition according to one of claims 1 to 5, further comprising a sizing. 7. The composition according to claim 6, in which the lubricant is magnesium stearate. 8. The composition according to one of claims 1 to 7, which contains from 0.01 to 20 wt.% Agonist receptor S1P. 9. The composition according to one of claims 1 to 8, containing from 0.5 to 5 wt.% S1P receptor agonist. 10. The composition according to one of claims 1 to 9, which contains from 75 to 99.99 wt.% Sugar alcohol. 11. The composition according to one of claims 1 to 10, containing from 90 to 99.5 wt.% Sugar alcohol. 12. The composition according to one of paragraphs.6-11, which contains from 0.01 to 5 wt.% Sizing. 13. The composition according to one of claims 6 to 9, containing from 1.5 to 2.5 wt.% Sizing. 14. The composition according to one of claims 1 to 13, in which the S1P receptor agonist is ground. 15. The composition according to one of claims 1 to 14, in which the S1P receptor agonist is pre-sieved through a sieve with mesh sizes from 400 to 500 microns. 16. The composition according to one of claims 1 to 15, in the form of a tablet or capsule. 17. The composition according to one of claims 1 to 16, intended for use in the manufacture of a medicament for the prevention or treatment of organ or tissue transplant rejection, transplant versus host disease, autoimmune disease, inflammatory conditions, viral myocarditis and viral diseases associated with viral myocarditis . 18. The composition according to one of claims 1 to 16, intended for use in the manufacture of a medicinal product for the treatment of multiple sclerosis.